Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial.

Abstract

BACKGROUND:

Preclinical data suggest that triple-negative breast cancers are sensitive to interstrand crosslinking agents, and that synergy may exist for the combination of a taxane, trastuzumab, and a platinum salt for HER2-positive breast cancer. We therefore aimed to assess the efficacy of the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive breast cancer.

METHODS:

Patients with previously untreated, non-metastatic, stage II-III, triple-negative breast cancer and HER2-positive breast cancer were enrolled. Patients were treated for 18 weeks with paclitaxel (80 mg/m(2) once a week) and non-pegylated liposomal doxorubicin (20 mg/m(2) once a week). Patients with triple-negative breast cancer received simultaneous bevacizumab (15 mg/kg intravenously every 3 weeks). Patients with HER2-positive disease received simultaneous trastuzumab (8 mg/kg initial dose with subsequent doses of 6 mg/kg intravenously every 3 weeks) and lapatinib (750 mg daily). Patients were randomly assigned in a 1:1 ratio with dynamic allocation and minimisation, stratified by biological subtype and Ki-67 level to receive, at the same time as the backbone regimens, either carboplatin (AUC 1·5 [2·0 for the first 329 patients] once a week) or no carboplatin. The primary endpoint the proportion of patients who achieved a pathological complete response (defined as ypT0 ypN0), analysed for all patients who started treatment; a p value of less than 0·2 was deemed significant for the primary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01426880.

FINDINGS:

296 patients were randomly assigned to receive carboplatin and 299 to no additional carboplatin, of whom 295 and 293 started treatment, respectively. In this final analysis, 129 patients (43·7%, 95% CI 38·1-49·4) in the carboplatin group achieved a pathological complete response, compared with 108 patients (36·9%, 31·3-42·4) without carboplatin (odds ratio 1·33, 95% CI 0·96-1·85; p=0·107). Of the patients with triple-negative breast cancer, 84 (53·2%, 54·4-60·9) of 158 patients achieved a pathological complete response with carboplatin, compared with 58 (36·9%, 29·4-44·5) of 157 without (p=0·005). Of the patients with HER2-positive tumours, 45 (32·8%, 25·0-40·7) of 137 patients achieved a pathological complete response with carboplatin compared with 50 (36·8%, 28·7-44·9) of 136 without (p=0·581; test for interaction p=0·015). Haematological and non-haematological toxic effects that were significantly more common in the carboplatin group than in the no-carboplatin group included grade 3 or 4 neutropenia (192 [65%] vs 79 [27%]), grade 3 or 4 anaemia (45 [15%] vs one [<1%]), grade 3 or 4 thrombocytopenia (42 [14%] vs one [<1%]), and grade 3 or 4 diarrhoea (51 [17%] vs 32 [11%]); carboplatin was more often associated with dose discontinuations (141 [48%] with carboplatin and 114 [39%] without carboplatin; p=0·031). The frequency of grade 3 or 4 haematological events decreased from 82% (n=135) to 70% (n=92) and grade 3 or 4 non-haematological events from 78% (n=128) to 59% (n=77) in the carboplatin arm when the dose of carboplatin was reduced from AUC 2·0 to 1·5.

INTERPRETATION:

The addition of neoadjuvant carboplatin to a regimen of a taxane, an anthracycline, and targeted therapy significantly increases the proportion of patients achieving a pathological complete response. This regimen seems to increase responses in patients with triple-negative breast cancer, but not in those with HER2-positive breast cancer.

FUNDING:

GlaxoSmithKline, Roche, and Teva.

• Authors: Gunter von Minckwitz, Andreas Schneeweiss, Sibylle Loibl, Christoph Salat, Carsten Denkert, Mahdi Rezai, Jens U Blohmer, Christian Jackisch, Stefan Paepke, Bernd Gerber, Dirk M Zahm, Sherko Kümmel, Holger Eidtmann, Peter Klare, Jens Huober, Serban Costa, Hans Tesch, Claus Hanusch, Jörn Hilfrich, Fariba Khandan, Peter A Fasching, Bruno V Sinn, Knut Engels, Keyur Mehta, Valentina Nekljudova, Michael Untch
• Journal: The Lancet. Oncology (Lancet Oncol) Vol. 15 Issue 7 Pg. 747-56 (Jun 2014) ISSN: 1474-5488 [Electronic] England
• PMID: 24794243 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Carboplatin
• ERBB2 protein, human
• Receptor, ErbB-2

Topics

• Adult
• Aged
• Antineoplastic Agents (therapeutic use)
• Carboplatin (adverse effects, therapeutic use)
• Female
• Humans
• Middle Aged
• Neoadjuvant Therapy
• Receptor, ErbB-2 (analysis)
• Triple Negative Breast Neoplasms (chemistry, drug therapy, pathology)